Process for the preparation of nizatidine

ABSTRACT

The present invention relates to a novel process for the preparation of nizatidine, N-[2-[[[2-(dimethylamino)methyl-4-thiazolyl]methyl]thio]ethyl]-N&#39;-methyl-2-nitro-1,1-ethenediamine, and pharmaceutically acceptable salts thereof, comprising reacting a compound of formula II ##STR1## with a compound of formula III ##STR2## or a salt thereof, in which X represents a leaving group, in the presence of methylamine in the presence of an inert diluent.

This application is a 371 of PCT/EP97/04705 filed Aug. 29, 1997.

The present invention relates to a novel process for the preparation ofnizatidine,N-[2-[[[2-(dimethylamino)methyl-4-thiazolyl]methyl]thio]ethyl]-N'-methyl-2-nitro-1,1-ethenediamine,and pharmaceutically acceptable salts thereof.

The preparation of nizatidine by fusing4-chloromethyl-2-dimethylaminomethylthiazole withN-(2-mercaptoethyl)-N'-methyl-2-nitro-1,1-ethenediamine has beensuggested generically in EP 49618. However, we have found thatN-(2-mercaptoethyl)-N'-methyl-2-nitro-1,1-ethenediamine cannot beisolated and stored. Our attempts to prepare this compound have alwaysproduced the disulphide,N-methyl-[N'-[2-(N"-methyl-2-nitro-1,1-ethenediamine)ethyldisulphanyl]ethyl]-2-nitro-1,1-ethenediamineand 3-methylamino-5,6-dihydro-[1,4]-thiazin-2-one oxime.

The present invention provides a novel process for the preparation ofnizatidine I ##STR3## and pharmaceutically acceptable salts thereof,comprising reacting a compound of formula II ##STR4## with a compound offormula III ##STR5## or a salt thereof, in which X represents a leavinggroup, in the presence of methylamine in the presence of an inertdiluent.

The present invention represents a considerable improvement, over theknown processes for the preparation of nizatidine, in that it allows aone-pot process with high yields, low production costs, fast processingtimes and avoids the problems of the known processes. In addition, theprocess of the present invention allows the possibility of an extremelycost-efficient continuous process.

The reactants involved in this process II, III and methylamine may bemixed in a number of different ways. In one embodiment of the presentinvention II and III or a salt thereof are combined to give a mixtureand methylamine is added to this mixture.

In a second embodiment II is combined with methylamine to give a mixtureand III or a salt thereof is added to the mixture. Optionally furthermethylamine is added as III or a salt thereof is added.

In a third embodiment II, III and methylamine are combined togethersimultaneously. Optionally further methylamine is added.

The second embodiment is preferred.

In a most preferred embodiment of the present invention the process iscontinuous and III or a salt thereof is added simultaneously withmethylamine to a reaction mixture comprising II and methylamine andafter a suitable time period the product is removed and the vessel isre-charged with reactants and the process is continued.

The term inert diluent as used herein means a liquid which is inert tothe reactants and products in the process under the conditions used inthe process. Any such liquid may be used. Preferably the inert diluentis water or an organic solvent selected from a nitrile, a C₁₋₈ alcohol,a halogenated alkane, an ether, N,N-dimethylformamide, dimethylsulphoxide and mixtures thereof. More preferably the inert diluent iswater, acetonitrile, methanol, ethanol, propanol, dichloromethane ortetrahydrofuran or mixtures thereof. Most preferably the inert diluentis acetonitrile or water or mixtures thereof.

Surprisingly it has been found that the process may be carried out inthe presence of water. This means that the process may be carried out ininert diluents which do not have to be rigorously dried. In additionaqueous solutions of methylamine may be used which are easier to use ona production scale than gaseous methylamine leading to cost savings.

The tolerance of the process to water also leads to considerableimprovements in the physical handling of the materials during theprocess. The use of water means that a salt of III may be added as asolution at ambient temperature thus eliminating the necessity ofheating to keep III in solution during the addition or the necessity ofusing acidic adjuncts which may corrode the reaction vessels.

The process may be carried out without batchwise addition of startingmaterials at set time intervals which is costly. Instead a simplecontinuous addition of reactants may be employed which is convenient touse, easy to control and may be scaled up to give an easy to operate andcost effective production process.

Suitably X represents a leaving group known to those skilled in the art,for example halo or a group of formula OR₁ in which R₁ represents

a) an optionally substituted C₁₋₆ alkyl group or an optionallysubstituted phenyl group or

b) a group of formula SO₂ R₂ or

c) a group of formula COR₂ or

d) a group of formula CO₂ R₂ ; in which R₂ represents an optionallysubstituted C₁₋₆ alkyl group or an optionally substituted phenyl group.Preferably X represents halo, mesyloxy or tosyloxy. More preferably Xrepresents chloro or bromo.

It will be understood by those skilled in the art that compounds offormula III may be prepared in situ without isolation, from knowncompounds, for example from the compound of formula III in which Xrepresent hydroxy, by methods known to those skilled in the art.

Suitable salts of the compound of formula III are the hydrochloride,hydrobromide, hydriodide, methanesulphonate, p-toluenesulphonate,sulphate, nitrate, acetate, phosphate, maleate, succinate, citrate,fumarate or tartrate salts. The salts may be mono-salts, e.g. thehydrochloride salt, or di-salts e.g. the dihydrochloride, ornon-stoichiometric salts. The salts may be used in the form of solvatesfor example as hydrates. Preferably the salts are hydrohalide saltsparticularly the hydrochloride and hydrobromide salts. Most preferablythe salt is the dihydrochloride salt.

Suitably the methylamine may be added by bubbling methylamine gas intothe inert diluent or alternatively solutions of methylamine in the inertdiluent may be added dropwise.

The compound of formula III or a salt thereof may be added as a slurryin the inert diluent, as a solution in the inert diluent or as a drysolid.

Suitably the process is carried out at a temperature in the range of -30to 100° C., preferably in the range of -10° C. to 50° C.

Preferably the process is carried out under a substantially oxygen freeatmosphere for example under nitrogen or under argon. The process may becarried out under pressure in the range of 1 to 5 atmospheres.Preferably the reaction is carried out at atmospheric pressure.

Suitably the molar ratio of compound II to compound III is in the range0.5:1 to 1:1.5. Preferably the molar ratio is approximately 0.8:1 to1:1.2. More preferably the molar ratio is approximately 0.9:1. Suitablythe methylamine is present in excess. Preferably 1 to 20 molarequivalents of methylamine are used with respect to the compound offormula III. More preferably at least 3 molar equivalents of methylamineare used when a salt of the compound of formula III is used. Mostpreferably 3-12 molar equivalents of methylamine are used.

Optionally the compound of formula I may be converted into apharmaceutically acceptable salt thereof by an additional step in whichthe compound of formula I is brought into contact with an acid bymethods known to those skilled in the art. Preferably nizatidine isreacted with hydrochloric acid to give the hydrochloride salt. thoseskilled in the art. Preferably nizatidine is reacted with hydrochloricacid to give the hydrochloride salt.

The invention is illustrated by the following non-limitative Examples.Novel compounds were characterised by Elemental Analysis and one or moreof the following spectroscopic techniques; nuclear magnetic resonance,infra-red and mass spectroscopy. Unless otherwise stated the startingmaterials used in the examples are commercially available and may beobtained by reference to the Fine Chemicals Directory.2-Nitromethylenethiazolidine may be obtained from Fine Organics, SealSands, Teeside.

EXAMPLE 1

A mixture of 2-nitromethylenethiazolidine (25.7 g) and acetonitrile (50ml) was stirred and heated at 40° C. under nitrogen. Methylamine gas(16.0 g) was passed into the stirred mixture over 45 minutes to give asolution. A slurry of 4-chloromethyl-2-dimethylaminomethylthiazolehydrochloride (40.0 g) (prepared as described in EP49618) inacetonitrile (50 ml) was added to the solution over a period of 4.5hours whilst methylamine gas was bubbled through the reaction mixturesuch that methylamine (38.3 g) was added over the period (totalmethylamine added was 54.3 g). The temperature of the reaction mixturevaried between 24 and 35° C. during the addition. After the addition,the mixture was diluted with acetonitrile (50 ml) and stirred at ambienttemperature for 17 hours. A solid was removed by filtration and thefiltrate was split into 2 equal portions.

Portion 1

The solution was evaporated to give a black oil which was partitionedbetween water (200 ml) and chloroform (200 ml). The separated chloroformphase was washed with saturated brine, then dried over magnesiumsulphate, filtered and evaporated to give a reddish oil which wasdissolved in acetone (200 ml), boiled under reflux, cooled to 40° C.,and then seeded with nizatidine. The mixture was left to stand at 0-5°C. for 64 hours. The mixture was filtered to give nizatidine (10.4 g,37%) m.p. 118-122° C. The structure was confirmed by ¹ H nmr. Theproduct was 95.4% pure by HPLC.

Portion 2

The mixture was evaporated to give an oil which was taken up inchloroform (200 ml) then washed with water (100 ml). The chloroformsolution was washed with brine (100 ml), dried over magnesium sulphate,and then concentrated under reduced pressure at 45° C. to give a brownoil. The oil was dissolved in acetone (200 ml) and activated charcoal(0.5 g) was added to the solution. The mixture was boiled under refluxfor 10 minutes, then cooled to 45° C. and filtered at this temperatureto remove the charcoal. The filtrate was cooled to 20° C., seeded withnizatidine (0.05 g), then cooled 0-5° C. for 45 minutes during whichtime crystallisation occurred. The mixture was filtered to givenizatidine (9.4 g, 32.2%) Found: C, 43.5; H, 6.25; N, 20.8; S, 19.3%.C₁₂ H₂₁ N₅ O₂ S₂ requires: C, 43.5; H, 6.4; N, 21.1; S, 19.3%.

EXAMPLE 2

A mixture of 2-nitromethylenethiazolidine (12.6 g) and acetonitrile(21.5 ml) was stirred and heated at 40° C. under argon. Methylamine(20.0 g of a 40% w/w aqueous solution) was added slowly over 30 minutesto the reaction mixture at 40° C. The mixture was cooled at ambienttemperature and further methylamine (23.6 g of 40% w/w aqueous solution)was added over 2.5 hours and a solution of4-chloromethyl-2-dimethylaminomethylthiazole dihydrochloride (25.0 g) inwater (30 ml) was added over 5.5 hours with the addition of the thiazolestarting simultaneously with the addition of the methylamine. Thereaction mixture was left to stir for a further 15 minutes and then wasconcentrated under reduced pressure. The solid obtained was dissolved inmethyl ethyl ketone (130 ml) and aqueous potassium carbonate solution(43 ml, 10% w/w). A further portion of methyl ethyl ketone and water (50ml) was added to aid dissolution. The mixture was warmed slightly toobtain a solution. The mixture was separated and the aqueous layer waswashed with methyl ethyl ketone (2×130 ml and then 1×50 ml). Thecombined organic layers were dried and evaporated under reduced pressureto yield crude nizatidine (approximately 25 g, 88% yield), which wasshown to be 93.7% pure by HPLC. The crude solid was dissolved indichloromethane (300 ml). The solution was washed with water (3×75 ml).The combined aqueous layer and the washings were back extracted withdichloromethane and the combined organic layers were concentrated underreduced pressure to give nizatidine (21.8 g, 76.8% yield) which wasshown to be 98.3% pure by HPLC. The solid was dissolved in ethanol (45ml) by warming on a steam bath. The solution was removed from the steambath, treated with activated charcoal (2.3 g) and the mixture was boiledfor a further 8 minutes. The mixture was hot filtered. The filtrate wascooled and filtered to give nizatidine (15.6 g, 55% yield) which wasshown to be 99.7% pure by HPLC.

EXAMPLE 3

A mixture of 2-nitromethylenethiazolidine (12.6 g) and water (30.0 ml)was stirred and heated at 40° C. under Argon. Methylamine (20.0 g of a40% w/w aqueous solution) was added slowly over 30 minutes to thereaction mixture at 40° C. The mixture was cooled at ambient temperatureand further methylamine (23.6 g of 40% w/w aqueous solution) was addedover 2.5 hours and a solution of4-chloromethyl-2-dimethylaminomethylthiazole dihydrochloride (25.0 g) inwater (30 ml) was added over 5.5 hours with the addition of the thiazolestarting simultaneously with the addition of the methylamine. Thereaction mixture was left to stir for a further 15 minutes and then wasconcentrated under reduced pressure. The solid obtained was dissolved ina mixture of methyl ethyl ketone (200 ml), aqueous potassium carbonatesolution (43 ml, 10% w/w). The mixture was warmed slightly to obtain asolution. The mixture was separated and the aqueous layer was washedwith methyl ethyl ketone (2×130 ml and then 1×100 ml). The combinedorganic layers were evaporated under reduced pressure to yield crudenizatidine (approximately 25.2 g), which was shown to be 89.4% pure byHPLC. The crude solid was dissolved in dichloromethane (300 ml). Thesolution was washed with water (3×75 ml). The combined aqueous layer andthe washings were back extracted with dichloromethane and the combinedorganic layers were dried and concentrated under reduced pressure togive nizatidine (21.1 g, 74.3% yield). The solid was dissolved inethanol (45 ml) by warming on a steam bath. The solution was removedfrom the steam bath treated with activated charcoal (2.3 g) and themixture was boiled for a further 8 minutes. The mixture was hotfiltered. The filtrate was cooled and filtered to give nizatidine (13.8g, 48% yield) which was shown to be 99.8% pure by HPLC.

EXAMPLE 4

A mixture of 2-nitromethylenethiazolidine (11.95 g) and acetonitrile(154 ml) was stirred and heated at 40° C. and then methylamine (31.7 mlof a 40% w/w aqueous solution) was added in one batch. A solution of4-chloromethyl-2-dimethylaminomethylthiazole dihydrochloride (21.5 g) inwater (21.5 ml) was added dropwise to the reaction mixture over 50minutes. The mixture was then stirred for 2.5 hours and then the solventwas removed under reduced pressure to give an oil. The oil was dissolvedin water (150 ml) and extracted with dichloromethane (3×150 ml). Thecombined extracts were dried and evaporated to give nizatidine (19.2 g,70.6% yield). The crude material was 86.8% pure by HPLC.

What is claimed is:
 1. A process for the preparation of nizatidine I##STR6## and pharmaceutically acceptable salts thereof, comprisingreacting a compound of formula II ##STR7## with a compound of formulaIII ##STR8## or a salt thereof, in which X represents a leaving group,in the presence of methylamine in the presence of an inert diluent.
 2. Aprocess according to claim 1 in which II is combined with methylamine togive a mixture and III or a salt thereof is added to the mixture.
 3. Aprocess according to claim 2 in which further methylamine is added asIII or a salt thereof is added to the mixture.
 4. A process according toclaim 1 in which the inert diluent is acetonitrile or water or mixturesthereof.
 5. A process according to a claim 1 in which X represents halo,mesyloxy or tosyloxy.
 6. A process according to claim 1 in which theprocess is carried out at a temperature in the range of -10° C. to 50°C.
 7. A process according to claim 1 in which the molar ratio ofcompound II to compound III is in the range 0.5:1 to 1:1.5.
 8. A processaccording to claim 1 in which 1 to 20 molar equivalents of methylamineare used with respect to the compound of formula III.